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Elucidation of physiological and pathological roles of TDP-43 through autophagic machinery

Research Project

Project/Area Number 18K07364
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 51030:Pathophysiologic neuroscience-related
Research InstitutionThe University of Tokyo

Principal Investigator

Hashimoto Tadafumi  東京大学, 大学院医学系研究科(医学部), 特任准教授 (30334337)

Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
KeywordsTDP-43 / FUS / 筋萎縮性側索硬化症 / 前頭側頭葉変性症 / TDP=43 / 前頭側頭葉型変性症 / 神経変性疾患 / オートファジー
Outline of Final Research Achievements

Aberrant accumulation of TDP-43 or FUS in the affected motor neurons of patients with amyotrophic lateral sclerosis (ALS) is a pathological feature of ALS, however the molecular mechanisms whereby TDP-43 induced the neurodegeneration remained unclear. Here, we found that ULK1 mRNA was interacted with TDP-43, and knockdown of TDP-43 reduced the level of protein of ULK1. Knockdown of TDP-43 also reduced the level of LC3-II, indicating that TDP-43 has an important role in the regulation of autophagy. Moreover, ULK1 deficient mice exhibited severer motor dysfunction in the AAV9-TDP-43 model. These data suggest that autophagy regulates neurodegeneration induced by TDP-43.

Academic Significance and Societal Importance of the Research Achievements

脊髄前角の運動ニューロンが変性脱落することにより、重篤な筋萎縮を引き起こす神経難病である筋萎縮性側索硬化症において、どのような機序で運動乳論が神経変性を起こすのか不明であった。本研究ではタンパク質の品質管理に重要な機構であるオートファジーが、TDP-43の神経毒性に関与することを明らかにした。この結果はこれまで根本治療薬のなかった筋萎縮性側索硬化症に、新たな治療標的を提供するものである。

Report

(4 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report
  • 2018 Research-status Report

Research Products

(25 results)

All 2021 2020 2019 2018 Other

All Int'l Joint Research (6 results) Journal Article (10 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 10 results,  Open Access: 8 results) Presentation (9 results) (of which Int'l Joint Research: 4 results)

  • [Int'l Joint Research] Cardiff University(英国)

    • Related Report
      2020 Annual Research Report
  • [Int'l Joint Research] Ludwig-Maximilians-University Munich(ドイツ)

    • Related Report
      2020 Annual Research Report
  • [Int'l Joint Research] Cardiff University(英国)

    • Related Report
      2019 Research-status Report
  • [Int'l Joint Research] Ludwig-Maximilians-University Munich(ドイツ)

    • Related Report
      2019 Research-status Report
  • [Int'l Joint Research] Cardiff University(英国)

    • Related Report
      2018 Research-status Report
  • [Int'l Joint Research] University of Nevada(米国)

    • Related Report
      2018 Research-status Report
  • [Journal Article] Long non-coding RNA NEAT1_1 ameliorates TDP-43 toxicity in in vivo models of TDP-43 proteinopathy2021

    • Author(s)
      Matsukawa Koji、Kukharsky Michail S.、Park Sei-Kyoung、Park Sangeun、Watanabe Naruaki、Iwatsubo Takeshi、Hashimoto Tadafumi、Liebman Susan W.、Shelkovnikova Tatyana A.
    • Journal Title

      RNA Biology

      Volume: 1 Pages: 1-9

    • DOI

      10.1080/15476286.2020.1860580

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Collagenous Alzheimer amyloid plaque component impacts on the compaction of amyloid-β plaques2020

    • Author(s)
      Hashimoto Tadafumi、Fujii Daisuke、Naka Yasushi、Kashiwagi-Hakozaki Mayu、Matsuo Yuko、Matsuura Yusuke、Wakabayashi Tomoko、Iwatsubo Takeshi
    • Journal Title

      Acta Neuropathologica Communications

      Volume: 8 Pages: 212-212

    • DOI

      10.1186/s40478-020-01075-5

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Behavioral and electrophysiological evidence for a neuroprotective role of aquaporin-4 in the 5xFAD transgenic mice model2020

    • Author(s)
      Abe Y, Ikegawa N, Yoshida K, Muramatsu K, Hattori S, Murakami M, Tanaka T, Goda W, Hashimoto T, Miyakawa T, Iwatsubo T, Hata J, Niikura T, Yasui M, et al.
    • Journal Title

      Acta Neuropathol. Commun.

      Volume: 8 Pages: 67-67

    • DOI

      10.1186/s40478-020-00936-3

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Differential effects of diet- and genetically-induced brain insulin resistance on amyloid pathology in a mouse model of Alzheimer's disease.2019

    • Author(s)
      Wakabayashi T, Yamaguchi K, Matsui K, Sano T, Kubota T, Hashimoto T, Mano A, Yamada K, Matsuo Y, Kubota N, Kadowaki T, Iwatsubo T
    • Journal Title

      Mol. Neurodegener.

      Volume: 14 Pages: 15-15

    • DOI

      10.1186/s13024-019-0315-7

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Characterization of the unique in vitro effects of unsaturated fatty acids on the formation of amyloid beta fibrils2019

    • Author(s)
      Miki Eto, Tadafumi Hashimoto, Takao Shimizu, Takeshi Iwatsubo
    • Journal Title

      PLOS One

      Volume: 14

    • DOI

      10.1371/journal.pone.0219465

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Calcium-responsive transactivator (CREST) toxicity is rescued by loss of PBP1/ATXN2 function in a novel yeast proteinopathy model and in transgenic flies2019

    • Author(s)
      Sangeun Park, Sei-Kyoung Park, Naruaki Watanabe, Tadafumi Hashimoto, Takeshi Iwatsubo, Tatyana A. Shelkovnikova, Susan W Liebman
    • Journal Title

      PLoS Genetics

      Volume: 15 Pages: 1-26

    • DOI

      10.1371/journal.pgen.1008308

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Roles of collagen XXV and its putative receptors PTP s/d in intramuscular motor innervation and congenital cranial dysinnervation disorder2019

    • Author(s)
      Haruka Munezane, Hiroaki Oizumi, Tomoko Wakabayashi, Shu Nishio, Tomoko Hirasawa, Takashi Sato, Akihiro Harada, Tomoyuki Yoshida, Takahiro Eguchi, Yuji Yamanashi, Tadafumi Hashimoto, Takeshi Iwatsubo
    • Journal Title

      Cell Reports

      Volume: 29 Pages: 4362-4376

    • DOI

      10.1016/j.celrep.2019.11.112

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Chronic cerebral hypoperfusion shifts the equilibrium of amyloid β oligomers to aggregation-prone species with higher molecular weight2019

    • Author(s)
      Bannai Taro、Mano Tatsuo、Chen Xigui、Ohtomo Gaku、Ohtomo Ryo、Tsuchida Takeyuki、Koshi-Mano Kagari、Hashimoto Tadafumi、Okazawa Hitoshi、Iwatsubo Takeshi、Tsuji Shoji、Toda Tatsushi、Iwata Atsushi
    • Journal Title

      Scientific Reports

      Volume: 9 Pages: 1-11

    • DOI

      10.1038/s41598-019-39494-7

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Self-assembly of FUS through its low-complexity domain contributes to neurodegeneration2018

    • Author(s)
      Taisei Matsumoto, Koji Matsukawa, Naruaki Watanabe, Yuya Kishino, Hayato Kunugi, Ryoko Ihara, Tomoko Wakabayashi, Tadafumi Hashimoto, Takeshi Iwatsubo
    • Journal Title

      Human Molecular Genetics

      Volume: 印刷中 Pages: 1353-1365

    • DOI

      10.1093/hmg/ddy046

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Patterns and severity of vascular amyloid in Alzheimer’s disease associated with duplications and missense mutations in APP gene, Down syndrome and sporadic Alzheimer’s disease2018

    • Author(s)
      Mann David M. A.、Davidson Yvonne S.、Robinson Andrew C.、Allen Nancy、Hashimoto Tadafumi、Richardson Anna、Jones Matthew、Snowden Julie S.、Pendleton Neil、Potier Marie-Claude、Laquerri?re Annie、Prasher Vee、Iwatsubo Takeshi、Strydom Andre
    • Journal Title

      Acta Neuropathologica

      Volume: 136 Pages: 569-587

    • DOI

      10.1007/s00401-018-1866-3

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Presentation] Soluble high-molecular weight oligomers of amyloid-beta peptide derived from the brains of APP transgenic mice induce cerebral amyloid-beta deposits2019

    • Author(s)
      Tadafumi Hashimoto, Yasushi Naka, Kashiwagi-Hakozaki Mayu, Tomoya Tajiri, Takeshi Iwatsubo
    • Organizer
      Neuroscience2019
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] Role of arginine methylation in the intercellular transmission of FUS2019

    • Author(s)
      Naruaki Watanabe, Koji Matsukawa, Mark Suarez-Calvet, Dorothee Dormann, Tadafumi Hashimoto, Takeshi Iwatsubo
    • Organizer
      Neuroscience2019
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] 脳内でβ―アミロイド蓄積を誘発する可溶な高分子量Aβオリゴマーの同定2019

    • Author(s)
      箱崎眞結、仲泰史、深山正久、牛久哲男、橋本唯史、岩坪威
    • Organizer
      第42回日本神経科学大会
    • Related Report
      2019 Research-status Report
  • [Presentation] ヒト型とマウス型apolipoprotein EがAβの凝集及び蓄積に与える影響の相違2019

    • Author(s)
      粉川明日香、大野裕太郎、橋本唯史、岩坪威
    • Organizer
      第42回日本神経科学大会
    • Related Report
      2019 Research-status Report
  • [Presentation] FUS induces neurodegeneration through its low-complexity domain in the drosophila retina.2018

    • Author(s)
      Tadafumi Hashimoto, Taisei Matsumoto, Yuya Kishino, Koji Matsukawa, Naruaki Watanabe, Tomoko Wakabayashi, Takeshi Iwatsubo
    • Organizer
      Neuroscience2018
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] Characterization of the seed Abeta oligomers in the brains of APP transgenic mice2018

    • Author(s)
      Mayu Hakozaki-Kashiwagi, Yasushi Naka, Tomohiko Tajiri, Masashi Fukayama, Tadafumi Hashimoto, Takeshi Iwatsubo
    • Organizer
      19th International Congress of Neuropathology
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] ヒト型とマウス型apolipoprotein EがAbeta脳内dynamicsに与える影響の相違2018

    • Author(s)
      粉川明日香、大野裕太郎、橋本唯史、岩坪威
    • Organizer
      第37回日本認知症学会
    • Related Report
      2018 Research-status Report
  • [Presentation] アミロイド斑蓄積のseedとして働く可溶性Abetaオリゴマーの同定2018

    • Author(s)
      箱崎眞結、仲泰史、田尻智也、深山正久、橋本唯史、岩坪威
    • Organizer
      第37回日本認知症学会
    • Related Report
      2018 Research-status Report
  • [Presentation] FUSの細胞間伝播機序に関する研究2018

    • Author(s)
      渡邊成晃、松川浩二、橋本唯史、岩坪威
    • Organizer
      第37回日本認知症学会
    • Related Report
      2018 Research-status Report

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Published: 2018-04-23   Modified: 2022-03-04  

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